Manufacture of 5-amino-1-pentanol and alkyl derivatives thereof



Patented July 25, 1950 UNITED: STATES PATENT omen MANUFACTURE OF 5 -AMINO e I-P-ENTANQL AND ALKYL DERIVATIVES RE OF John F. Olin, Grosselle, Mich3, assignor'to Sharples Chemicals 1110., Philadelphia, Pa., a corporation of Delaware 7 No-Drawing. Application May 28, 1946,

. SeriaLNo. 672,909

condensed with phthalimide and the product is then hydrolyzed, or, alternatively, the dihalide is reacted with silver nitrite and the resulting nitro group is then reduced to form the desired amino alcohol. When an N-substituted amino alcohol is required, its synthesis by a series of classical steps is even more involved and expensive, and, in fact, very, few 5-alkylamino-1- pentanols are reported in the literature. Such compounds are, nevertheless, of great value, particularly as intermediates in the preparation of' anti-malarials and other pharmaceuticals.

I have discovered that these products can be prepared simply and in good yield by the reductive amination of Z-hydroxypentamethylene oxide. My reaction. may be illustrated by the following chemical equation:

R o-om-om-omom-onon HN/ Hi B HooHn -N wherein R and R are chosen from the class consisting of hydrogen and. alkyl radicals. The reaction may be catalyzed by the use of any effective hydrogenation. catalyst, for, example, nickel, platinum, palladiumor cobalt-1 V In the practice of my process a suitable pres; sure-resistant vessel may be charged, for instance, with 1.5 gram moles oil amine and 30 grams of Raney nickel. Hydrogen" is then introduced until the pressure reaches about 1000 pounds per square inch, and the contents are heated with agitation to a temperature between 1 and; 125 01 One gram mole of. Z-hyd-roxypentamethylene oxide is then: introduced progressively; the said, temperature being maintained and make up hydrogen being introduced until no further tendency to absorb hydrogen is apparent. The contents are cooled,- res-idualhydrogen is eliminated by venting, the catalyst is separatedby filtration and finally the product is purified by fractional distillation in vacuo. The corresponding 5-alkylamino-l-pentanol is thus recovered in exceptionally pure form and in yields which generally fall between 70% and 95% depending upon the particular amine entering into;

2. the reaction; By an entirely analogous: pro,- cedure ammonia: may be used; instead ofthealkyl; amine to give approximately a 90%, yield; of; S-amino-l-pentanol.

The 2-hydroxypenta-methylene; oxide; may 0011': veniently; be, prepared by; the: procedultc' Qfi R... Paul; Bull. Soc. (Shim; (3)2, 1, 971-80 193 4;), which essentially- -compr-isess the hydration of; dihydropyrane. Since dihydropyrane; is known, to be easilyprepared from; tetrahydrofurfur-yl alcohol by catalytic dehydration; the processor, the present invention. makes it; possibletormanl tfacture valuable and-heretofore expensive amino-1. pentanols from relatively, plentiful raw'matenials, by the-followingsequence:

Ah 0 3 Tetrahydrofurfuryl alcohol dihydfiipyrane 2-hydroxypentamethylene oxide aminopentanol I Nitrogen base It. is noteworthy that. overall yieldsvbased upon; the tetrahydroi-urfuryl, alcohol are, generallyv above andarefreqllentlyabove 6.5%.,

The nitrogen=containing bases. which, aresuitable for the-practice of my invention are those, having th structure.

a HN/ wherein R. and B," may be hydrogen or alley]; groups. Thus are included ammonia, dimethyl monomethyl diet'hyl monoethyb, methyle ethyl-,, isopropyl-,, di-isopropylr, bntyl amyl and hexyl-amine, and, in fact any; primary or;

secondary alkylamine, any alkyl substituent of which may contain from one to sixteen or more carbon. atoms. v

The reductive amination reaction of the: PIGS! ent invention. may be practiced under conditions: which varywconsiderably'from those hereinbeilore; recited; Thus the, reaction may be conductedaft-temperatures limited-a only on the-one handby;

the activity of th catalyst: and, on: theothen, by:

the stability of the product and? the; reactants, Bya suitable selection of hyd-rogenating catalyst, chosen 'from'the hydrogenating metals; metal oxides and salts known to; th art, t:.emperati res;v ranging fronrZO C; to200 maybe successiuiiy mpl yed. Thepressure exerted yt eh dr sen not critical, highpressures;v merely tending;

expedite: the reaction.

moderate excess. of amine generally employed: although: it; is feasible to operate, with, an, excess or the hydroxypentamethylene oxides, It optimum yields are to be; obtain d, he. hydro ypentamethylene oxide should not be subjected to hydrogenating conditions in the absence of substantial proportions of amine or ammonia. For example, the reactants may be introduced consecutively or substantially concurrently into a batchwise-reaction system, or they may be caused to flow concurrently through a system of the continuous type. Inert solvents may be employed if desired. In the isolation of the desired amino alcohol distillation is suitable for those products which are of suificient thermal stability and volatility, but it is obvious that other known procedures may be employed and indeed, in certain instances, may be preferable.

The following examples will further illustrate various aspects of my invention:

Example 1 1850 grams of isopropylamine, 100 grams of Raney nickel catalyst and 500 ml. of methanol were placed in a 2 gallon autoclave with hydrogen at 500 pounds 'per square inch and were heated to 116 C. with agitation. At that temperature 1850 grams of Z-hydroxypentamethylene oxide were pumped in over a period of minutes. Hydrogen was added at intervals to maintain a pressure of 700-1000 pounds per square inch, Heating'and stirring were-continued until there wasno further drop inpressure (15 minutes). The autoclave was cooled, and its contents were discharged and filtered, and then distilled through a fractionating column to yield 2082 grams of 5-isopropylamino-l-pentanol. This amounts to a conversion of 79% based on the oxide. The product distilled between 120 and 125 C. at 12 mm. and solidified at 45 C.

' Example 2 Example 3 By the procedure of Example 1, the reaction using 1971 grams of diethylamine, 100 grams Raney nickel catalyst, 1,5-30 grams of 2-hydroxypentamethylene oxide and hydrogen gave 2,208 grams of 5-diethylamino-l-pentanol, distilling between 124 and 129 C. at mm. The conversion was 92.2%.

. Example 4 Y By the procedure of Example 1, 765. grams of ammonia, 1530 grams of '2-hydroxypentamethylene oxide and hydrogen were reacted in the presence of 100-grams of Raney nickel catalyst and 300 ml. of'm'ethanol. The initial pressure was 800 pounds per square inch and the maximum was about 1,250 pounds per square inch during the reaction. Distillation of the crude product gave 1,349 grams of 5-amino-1-pentanol, which distilled between 119 and 122 C. at 18 mm. The conversion amounted to 87.3%.

While the invention has' been described primarily with reference to aprocess in which the hydrogen is present during the entire condensation reaction, it may be practiced by an alternative procedure in which the ammonia or amine is first condensed with the 2-hydroxypentamethylene oxide and the resulting condensation product thereafter hydrogenated. The following ex- 4 ample illustrates the practice of the invention by this sequence of steps.

Emample 5 679 grams of crude 2-hydroxypentamethylene oxide, 1,500 ml. of hexane and 360 grams of isopropylamine were mixed and refluxed 30 minutes. Water (87 ml.) was formed and was separated. The oil layer was then hydrogenated in the presence of 300 grams of Raney nickel catalyst at LOGO-1,275 pounds per square inch hydrcgen pressure and at a temperature of 70-100 C. The reaction required 30 minutes. The catalyst was filtered off and the solvent removed by distillation. Fractionation of the residue gave two cuts, grams of an impure fraction containing substantial quantities of 5-isopropylamino-l-pentanol and 197 grams of pure 5-isopropylamino-l-pentanol boiling between 123-125 C. at 12 mm. Hg pressure and solidifying at Since various modifications are available within the scope of the invention, I do not wish to be'limited except by the scope of the following claims:

I claim: 1 q

1. In the preparation of amino alcohols of the structure the process comprising reacting Z-hydroxypentamethylene oxide with a compound of the structure wherein R and R are chosen from the class consisting of hydrogen and alkyl radicals having less than 17 carbon atoms, and with hydrogen, said reaction taking place under elevated pressure conditions and in the presence of a hydrogenatingcatalyst.

2. In the preparation of amino alcohols of the structure the process comprising reacting Z-hydroxypentamethylene oxide with a compound of the struc-' ture HIN wherein R. and R. are chosen from the class consisting of hydrogen and alkyl radicals having less than 17 carbon atoms-and with hydrogen, said reaction taking place under elevated temperature and pressure conditions and in the presenceof a hydrogenating catalyst.

3. In the preparation of amino alcohols of the structure the process comprising reacting Zahydroxypenta methylene oxide with a compound of the structure N- cHm-on R! the process comprising reacting Z-hydroxypentamethylene oxide with a compound of the structure wherein R and R. are chosen from the class consisting of hydrogen and alkyl radicals having less than 1'7 carbon atoms, and with hydrogen, said reaction taking place under elevated pressure conditions in the presence of a hydrogenating catalyst and at a temperature between 30 and 200 C.

5. In the preparation of 5-isopropylamino-1- pentanol, the process comprising reacting 2-hydroxypentamethylene oxide with isopropylamine and hydrogen, said reaction taking place under elevated temperature and pressure conditions and in the presence of a hydrogenating catalyst.

6. In the preparation of 5-diethylamino-1- pentanol, the process comprising reacting 2-hydroxypentamethylene oxide with diethylamine and hydrogen, said reaction taking place under elevated temperature and pressure conditions and a in the presence of a hydrogenating catalyst.

7. In the preparation of 5-amino-1-pentanol, the process comprising reacting 2-hydroxypentamethylene oxide with ammonia and hydrogen, said reaction taking place under elevated temperature and pressure conditions and in the presence of a hydrogenating catalyst.

8. In the preparation of amino alcohols of the structure --(GH1)5--OH the process comprising condensing 2-hydroxypentamethylene oxide with a compound of the structure R HN/ wherein R and R are chosen from the class consisting of hydrogen and alkyl radicals having less than 17 carbon atoms, and thereafter hydrogenating the resulting condensation product in the presence of a hydrogenating catalyst and under elevated temperature and pressure conditions.

9. In the preparation of amino alcohols of the structure \N(CH2)5-OH the process comprising reacting 2-hydroxypentanethylene oxide with a compound of the strucure wherein R and R are chosen from the class consisting of hydrogen and alkyl radicals having less than 17 carbon atoms, and with hydrogen, the reaction being performed by maintaining the compound of the structure under pressure of hydrogen and introducing the Z-hydroxypentamethylene oxide into said compound while said last-mentioned compound is under said hydrogen pressure.

10. The process of claim 9 in which the compound of the structure is maintained present in the zone of reaction in stoichiometric excess with respect to the 2-hydroxypentamethylene oxide throughout the reaction.

JOHN F. OLIN.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,182,087 Hasche Dec. 12, 1939 2,349,222 Goshorn May 16, 1944 2,365,825 Kyrides Dec. 26, 1944 FOREIGN PATENTS Number Country Date 415,691 Great Britain Nov. 23, 1932 OTHER REFERENCES Pa-ul, Bull. soc. chim. (5) vol. 1, pages 971- 980 (1934).

Adkins, Reactions of Hydrogen, Univ. of Wis. Press, page 135. 

1. IN THE PREPARATION OF AMINO ALCOHOLS OF THE STRUCTURE 